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Fatty Acid Degradation (FAD) Subtype-Informed Treatment Allocation in Unresectable Hepatocellular Carcinoma (FAD-HCC-01): Protocol for a Prospective Multicentre Proof-of-Concept Study
J Hepatocell Carcinoma. 2026 May 15;13:608436. doi: 10.2147/JHC.S608436. eCollection 2026.
ABSTRACT
BACKGROUND: Hepatocellular carcinoma (HCC) exhibits substantial biological and metabolic heterogeneity, contributing to variable therapeutic responses in unresectable disease. Although immune checkpoint inhibitors combined with anti-angiogenic agents have improved outcomes, treatment selection remains largely empirical because validated predictive biomarkers are lacking. Recent multi-omics studies have identified fatty acid degradation (FAD)-related transcriptional signatures that classify HCC into distinct metabolic subtypes with different immune microenvironment characteristics and therapeutic vulnerabilities. Retrospective analyses suggest that F1/F2 subtypes may derive greater benefit from immune checkpoint inhibitor-based systemic therapy, whereas F3 tumours may be more responsive to transarterial chemoembolisation (TACE). However, whether FAD-based metabolic stratification can prospectively inform treatment allocation remains unknown.
METHODS: FAD-HCC-01 is a prospective, multicentre, open-label proof-of-concept Phase II study designed to evaluate the feasibility and preliminary clinical activity of FAD-informed treatment allocation in patients with unresectable HCC. Eligible patients with Barcelona Clinic Liver Cancer stage B or C disease and no prior systemic therapy will undergo baseline tumour transcriptomic profiling to determine FAD subtype. Patients with F1/F2 tumours will receive camrelizumab plus rivoceranib, whereas patients with F3 tumours will receive TACE combined with camrelizumab and rivoceranib. Eighty-six patients will be enrolled, with 43 in each biomarker-defined cohort. The primary endpoint is objective response rate according to RECIST version 1.1. Secondary endpoints include objective response rate by mRECIST, disease control rate, progression-free survival, overall survival, duration of response, conversion to curative treatment, and safety. Exploratory analyses will assess concordance between MRI-derived proton density fat fraction and transcriptomic FAD classification.
CONCLUSION: This proof-of-concept study will prospectively assess whether FAD-based metabolic subtyping can inform treatment allocation in unresectable HCC. The results may provide early evidence supporting metabolism-informed precision therapy and the design of future biomarker-guided clinical trials.
PMID:42164571 | PMC:PMC13186218 | DOI:10.2147/JHC.S608436
HOX code-based stratification reveals RUNX1T1-HDAC reprogramming as a targetable driver of lineage plasticity across cancers
Cancer Lett. 2026 Mar 28;648:218465. doi: 10.1016/j.canlet.2026.218465. Online ahead of print.
ABSTRACT
Cancer remains a leading cause of death worldwide, with lineage plasticity emerging as a hallmark that drives therapy resistance and tumor progression by enabling cancer cells to alter identity and evade targeted therapies. Although genomic and transcriptomic aberrations correlate with lineage plasticity, the absence of scalable cross-cancer markers to rapidly identify plastic subtypes has limited predictive utility. Homeobox (HOX) genes encode transcription factors that define tissue identity through distinct expression patterns, or HOX codes, within specific lineages. By analyzing multi-omics data encompassing 39 HOX genes across more than 80,000 RNA-seq samples across 23 cancer types spanning 114 cancer subtypes, we found that HOX code expression robustly stratifies lineage-constrained and lineage-plastic states at a cross-cancer level. This framework revealed previously unrecognized lineage-plastic subtypes in prostate cancer, lung cancer, and acute myeloid leukemia (AML), each displaying distinct HOX code divergence compared to non-plastic counterparts. Differential expression analysis across these representative malignancies identified RUNX1T1 as a consistent regulator associated with HOX-defined plastic states. We validated RUNX1T1 upregulation in bulk and single-cell RNA-seq from extensive preclinical and clinical cohorts and demonstrated that RUNX1T1 is functionally required for lineage-plastic programs in prostate cancer models. AI-based structural modeling and co-immunoprecipitation established the NCOR/HDAC3 complex as a critical binding partner of RUNX1T1. CUT&RUN profiling revealed that RUNX1T1 remodels chromatin by globally reducing active enhancer marks, thereby repressing lineage-defining differentiation programs and reshaping HOX positional identity. Selective pharmacologic inhibition of HDAC3 or targeted gene silencing via lipid nanoparticles suppressed the growth of lineage-plastic cancer cells, uncovering a therapeutically actionable vulnerability. Together, these findings establish RUNX1T1 as a cross-lineage regulator of HOX code-defined plasticity and identify the RUNX1T1-HDAC axis as a targetable mechanism underlying cancer lineage plasticity.
PMID:41912135 | DOI:10.1016/j.canlet.2026.218465
HOX Code-Based Stratification Reveals RUNX1T1-HDAC Reprogramming as a Targetable Driver of Lineage Plasticity Across Cancers
Cancer Lett. 2026 Mar 28:218465. doi: 10.1016/j.canlet.2026.218465. Online ahead of print.
ABSTRACT
Cancer remains a leading cause of death worldwide, with lineage plasticity emerging as a hallmark that drives therapy resistance and tumor progression by enabling cancer cells to alter identity and evade targeted therapies. Although genomic and transcriptomic aberrations correlate with lineage plasticity, the absence of scalable cross-cancer markers to rapidly identify plastic subtypes has limited predictive utility. Homeobox (HOX) genes encode transcription factors that define tissue identity through distinct expression patterns, or HOX codes, within specific lineages. By analyzing multi-omics data encompassing 39 HOX genes across more than 80,000 RNA-seq samples across 23 cancer types spanning 114 cancer subtypes, we found that HOX code expression robustly stratifies lineage-constrained and lineage-plastic states at a cross-cancer level. This framework revealed previously unrecognized lineage-plastic subtypes in prostate cancer, lung cancer, and acute myeloid leukemia (AML), each displaying distinct HOX code divergence compared to non-plastic counterparts. Differential expression analysis across these representative malignancies identified RUNX1T1 as a consistent regulator associated with HOX-defined plastic states. We validated RUNX1T1 upregulation in bulk and single-cell RNA-seq from extensive preclinical and clinical cohorts and demonstrated that RUNX1T1 is functionally required for lineage-plastic programs in prostate cancer models. AI-based structural modeling and co-immunoprecipitation established the NCOR/HDAC3 complex as a critical binding partner of RUNX1T1. CUT&RUN profiling revealed that RUNX1T1 remodels chromatin by globally reducing active enhancer marks, thereby repressing lineage-defining differentiation programs and reshaping HOX positional identity. Selective pharmacologic inhibition of HDAC3 or targeted gene silencing via lipid nanoparticles suppressed the growth of lineage-plastic cancer cells, uncovering a therapeutically actionable vulnerability. Together, these findings establish RUNX1T1 as a cross-lineage regulator of HOX code-defined plasticity and identify the RUNX1T1-HDAC axis as a targetable mechanism underlying cancer lineage plasticity.
PMID:41912135 | DOI:10.1016/j.canlet.2026.218465